Mirong Guan

Structural Effect and Mechanism of C70‐Carboxyfullerenes as Efficient Sensitizers against Cancer Cells

Carboxyfullerenes with different adduct numbers and cage sizes are tested as photosensitizers for photodynamic therapy (PDT). The photodynamic efficiency of these carboxyfullerenes depends mainly on the cage size, C(60) versus C(70) , and to a lesser extent on the adduct numbers. In particular, malonic acid modified C(70) fullerenes are more efficient than their C(60) counterparts as photosensitizers, and the mechanism of cell death induced by C(70) -carboxyfullerene under light irradiation is investigated in detail. The results indicate that cell death occurs via necrosis accompanied by membrane blebbing, which is a unique phenomenon for photosensitizer-induced cell death. Since C(70) -carboxyfullerene displays an efficient PDT property and negligible dark cytotoxicity, it is promising for use in PDT applications, especially in vascular capillary diseases usually occurring under the surface.

Amphiphilic trismethylpyridylporphyrin-fullerene (C70) dyad: an efficient photosensitizer under hypoxia conditions

Amphiphilic trismethylpyridylporphyrin-C70 (PC70) dyad with improved photosensitization has been successfully prepared. The PC70 dyad forms a liposomal nanostructure through molecular self-assembling. An increased absorption coefficient in the visible region, good biocompatibility, and high photostability were observed on the self-assembling structure. Surprisingly, in comparison with previously reported photosensitizer porphyrins, PC70 exhibited an enhanced photodynamic therapy (PDT) effect under hypoxia conditions. Further investigations illustrated that PC70 went through an extremely long-life triplet state (211.3 μs) under hypoxia, which enabled the exiguous oxygen to approach and interact with the activated (3P-C70)* more efficiently and produce more singlet oxygen. This would overcome the problem of existing photosensitizers of low PDT efficiency in cancerous tissues under hypoxia. The excellent properties of PC70 dyad make it a promising phototherapeutic agent, especially for the treatment of early- and late-stage cancers under shallow and hypoxia tissues.

Effects of fullerene derivatives on bioluminescence and application for protease detection

The effects of two C(60) derivatives: C(60)[C(COOH)(2)](3) and C(60)(NH(2))(x)(OH)(y), have been investigated on the bioluminescence of humanized Gaussia luciferase (hGluc) for the first time. Utilizing the dual properties of carboxyl C(60) with luminescence quenching and free radicals scavenging, a novel BRET system was constructed for protease detection with high sensitivity.

Protective effect of C70-carboxyfullerene against oxidative-induced stress on postmitotic muscle cells.

Satellite muscle cells play an important role in regeneration of skeletal muscle. However, they are particularly vulnerable to oxidative stress. Herein, we address our efforts on the cytoprotective activities of carboxyfullerenes with different cage size (C60 vs C70) and adduct number on postmitotic muscle cell (C2C12 cell). The correlation of the structural effect on the cytoprotective capability of carboxyfullerenes was evaluated. We find that quadri-malonic acid C70 fullerene (QF70) exhibits higher capability on protecting cells from oxidative-induced stress among these tested carboxyfullerenes. The accumulation of intracellular superoxide dismutase (SOD) is proposed to play an important role in their diverse antioxidative ability. Moreover, the pretreatment of QF70 could also obviously enhance the viability of myotubes originated from oxidative-stressed C2C12 cells, which facilitates the future application of carboxyfullerenes in tissue engineering and nanomedicine.

Synergistic Effect of Human Serum Albumin and Fullerene on Gd-DO3A for Tumor-Targeting Imaging

A macromolecular magnetic resonance imaging (MRI) contrast agent was successfully synthesized by conjugating the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic acid complex (Gd-DO3A) with 6,6-phenyl-C61 butyric acid (PC61BA) and upon further modification with human serum albumin (HSA). The final product, PC61BA-(Gd-DO3A)/HSA, has a high stability and exhibits a much higher relaxivity (r1 = 89.1 mM(-1) s(-1) at 0.5 T, 300 K) than Gd-DO3A (r1 = 4.7 mM(-1) s(-1)) does under the same condition, producing the synergistic positive effect of HSA and C60 on the relaxivity of Gd-DO3A. The in vivo MR images of PC61BA-(Gd-DO3A)/HSA-treated tumor-bearing mice show strong signal enhancement for the tumor area due to the enhanced permeability and retention effect. The maximum accumulation of PC61BA-(Gd-DO3A)/HSA at the tumor site was achieved at 4 h postinjection, which may guide surgery. The results from the hematology and histological observations indicate that PC61BA-(Gd-DO3A)/HSA has no obvious toxicity in vivo. These unique properties of PC61BA-(Gd-DO3A)/HSA enable them to be highly efficient for tumor-targeting MRI in vivo, possibly providing a good solution for tumor diagnosis.

Enhanced Photodynamic Efficiency of an Aptamer-Guided Fullerene Photosensitizer toward Tumor Cells

Fullerene-based photosensitizers exhibit great potential in photodynamic therapy (PDT). Based on the high photodynamic efficacy of trimalonic acid-modified C70 fullerene (TF70), we constructed an aptamer-guided TF70 photosensitizer and investigated its photodynamic effect. Conjugation of the novel aptamer (named R13) could effectively enhance the PDT efficiency of TF70 against A549 lung cancer cells in the presence of serum. The lysosomal location of the TF70-R13 conjugate inside cells facilitates the production of intracellular reactive oxygen species (ROS), which can efficiently kill cells, under light irradiation. The enhanced photodynamic efficiency, along with its good biocompatibility in the dark, makes TF70-R13 a highly promising photosensitizer for tumor-specific PDT.

C70-carboxyfullerenes as efficient antioxidants to protect cells against oxidative-induced stress.

Oxidative stress induced by excessive production of reactive oxygen species (ROS) has been implicated in the etiology of many human diseases. Acquiring a highly efficient antioxidant with good biocompatibility is of significance in eliminating the deleterious effect induced by the oxidative stress. Herein, we address our efforts on investigating the cytoprotective effect of carboxyfullerenes on H2O2-injured cells. Meanwhile, the uptake and intracellular location of carboxyfullerenes were studied. The results show that C70-carboxyfullerenes (dimalonic acid C70 fullerene (DF70) and trimalonic acid C70 fullerene (TF70)) exhibit an obviously protective effect against oxidative stress on C2C12 cells at concentrations as low as 2.5 μmol L(-1), whereas C60-carboxyfullerenes (dimalonic acid C60 fullerene (DF60) and quadri-malonic acid C60 fullerene (QF60)) show a protective effect at relatively higher concentration (40 μmol L(-1)). The molecular structure of carboxyfullerenes and the physiological state of cells play an important role in the different cytoprotective capability. Further study reveals that DF70 and TF70 could enter into cells and mainly localize into the lysosome, which possibly involves the protective mechanism by stabilizing lysosome. The use of a significantly low concentration of C70-carboxyfullerene as the antioxidative agent will benefit the therapeutic approaches aiming at alleviating ROS-induced injuries such as muscle disorder and arthritis.

A Versatile and Clearable Nanocarbon Theranostic Based on Carbon Dots and Gadolinium Metallofullerene Nanocrystals

Nanocarbons such as carbon nanotubes, graphene derivatives, and carbon nanohorns have illustrated their potential uses as cancer theranostics owing to their intrinsic fluorescence or NIR absorbance as well as superior cargo loading capacity. However, some problems still need to be addressed, such as the fates and long-term toxicology of different nanocarbons in vivo and the improvement of their performance in various biomedical imaging-guided cancer therapy systems. Herein, a versatile and clearable nanocarbon theranostic based on carbon dots (CDs) and gadolinium metallofullerene nanocrystals (GFNCs) is first developed, in which GFNCs enhance the tumor accumulation of CDs, and CDs enhance the relaxivity of GFNCs, leading to an efficient multimodal imaging-guided photodynamic therapy in vivo without obvious long-term toxicity. Furthermore, biochemical analysis reveals that the novel nanotheranostic can harmlessly eliminate from the body in a reasonable period of time after exerting diagnostic and therapeutic function.

Biodegradable, Hydrogen Peroxide, and Glutathione Dual Responsive Nanoparticles for Potential Programmable Paclitaxel Release

Reactive oxygen species (ROS) and glutathione (GSH) dual responsive nanoparticulate drug delivery systems (nano-DDSs) hold great promise to improve the therapeutic efficacy and alleviate the side effects of chemo drugs in cancer theranosis. Herein, hydrogen peroxide (H2O2) and GSH dual responsive thioketal nanoparticle (TKN) was rationally designed for paclitaxel (PTX) delivery. Compared to other stimuli-sensitive nano-DDSs, this dual responsive DDS is not only sensitive to biologically relevant H2O2 and GSH for on-demand drug release but also biodegradable into biocompatible byproducts after fulfilling its delivering task. Considering the heterogeneous redox potential gradient, the PTX loaded TKNs (PTX-TKNs) might first respond to the extracellular ROS and then to the intracellular GSH, achieving a programmable release of PTX at the tumor site. The selective toxicity of PTX-TKNs to tumor cells with high levels of ROS and GSH was verified both in vitro and in vivo.

Amino acid functionalized gadofullerene nanoparticles with superior antitumor activity via destruction of tumor vasculature in vivo

Researchers have been puzzled of the therapy of malignant tumors and the current therapeutic strategies are always accompanied by toxicity or side effects. Developing efficient nanodrugs could reduce the dosage and greatly improve the therapeutic effects in cancer treatments. Here we initially reported a novel kind of gadofullerene nanoparticles functionalized with amino acid (β-alanine), which exhibited a superior antitumor activity in hepatoma H22 models via a novel therapeutic mechanism. The involvement of β-alanine improved the tumor inhibition rate up to 76.85% for a single treatment by strengthening the interaction with radiofrequency (RF) and extending blood circulation time. It realized a highly antivascular treatment to cut off the nutrient supply of tumor cells by physically destroying the abnormal tumor blood vessels assisted by RF. In situ and real-time observation of the vascular change was conducted using the dorsal skin fold chamber model, which corresponded to the erythrocyte diapedesis in histopathological examination. The ultrastructural changes of vascular endothelial cells were further investigated by environmental scanning electron microscopy and transmission electron microscopy. Long-term toxicity evaluation showed that the GF-Ala nanoparticles could be eliminated from the mice after several days and no obvious toxicity was found to the main organs. All these encouraging results suggest GF-Ala nanoparticles are valuable for the significant therapeutic potential with high-efficacy and low-toxicity.